Cyanohydrin process

ABSTRACT

Using cyanohydrin intermediates, 17-keto steroids are transformed to corticoids and 17α-acyl progesterones.

BACKGROUND OF THE INVENTION

There are a number of chemical processes for transformation of 17-ketosteroids to the corresponding 17α-hydroxypregna steroids, see U.S. Pat.No. 4,041,055 and Tetrahedron Letters 22, 2005 (1971). Likewise,chemical processes are known for the transformation of 17-keto steriodsto the corresponding corticoids, see U.S. Pat. Nos. 4,041,055,4,342,702, 4,216,159, and Great Britain Pat. No. 2,086,907A.

The literature also sets forth processes for the transformation of the17β-cyano-17α-hydroxy steroid (I) to the corresponding17α-acyloxyprogesterone (VI) see P. deRuggieri, et al., J. Am. Chem.Soc. 81, 5725 (1959); J. C. Gasc, et al., Tetrahedron Letters 22, 2005(1971); A. Belanger, Steroids 37, 361 (1981); and Japanese Pat. Nos. J57,062,296, J5 7,062,297, J5 7,062,299 and J5 7,062,300.

17β-Cyano-17α-hydroxy steroids (I) have been produced from thecorresponding 17-keto steroids, see A. Ercoli, et al., J. Am. Chem. Soc.75, 650 (1953); H. Heusser, et al., Helv. Chem. Acta 33, 1093 (1950); K.Meyer, Helv. Chim. Acta 29, 1580 (1946); K. Miescher, et al., Helv.Chim. Acta 21, 1317 (1938); H. Kuhl, et al., Steroids 28, 89 (1976),U.S. Pat. No. 3,496,169 and East German Pat. No. 147,669. Japanese Pat.Nos. J5 7,062,296, J5 7,062,299 and J5 7,062,300 also include17β-cyano-17α-hydroxyandrost-4,9(11)-dienes (IA). J. C. Gasc, et al.,Tetrahedron Letters 22, 2005 (1971) reported the preparation of19-nor-17β-cyano-17α-hydroxyandrost-5(10),9(11)-dienes.

17β-Cyano-17α-hydroxy steroids (I) are known where the 17α-hydroxy groupis protected as an ester. See, for example, Helv. Chem. Acta 29, 1580(1946) formula IV on p. 1582 and Helv. Chem. Acta 33, 1093 (1950)formula XIII on p. 1096. These compounds are also known where the17α-hydroxy group is protected as an ether (II). See, for example,Steroids 37, 362 (1981) on p. 362 the TMS ether; J. Am. Chem. Soc. 81,5725 (1959) on p. 5726 formula III as the THP ether; Tetra. Lett. 22,2005 (1971) on p. 2007 formula IX as the TMS ether; and Japanese Pat.No. 7,062,296 for the butyl vinyl ether. U.S. Pat. No. 4,348,327discloses 17β-cyano-17α-hydroxy steroids of the Δ⁴ -3-keto (A) and3β-hydroxy-Δ⁵ (C) type which may or may not have methyl substitution atC₁₆ but which have no substitution in the C ring.

D. H. R. Barton, et al., J.C.S. Chem. Comm. 774 (1981) reportedproducing a 3β-O-substituted-Δ⁵ -enimide similar to the enimide (III)where the protecting group at 17α was acetate and the substituent on theenimide nitrogen at C₂₀ was --CHO. It should be noted that Barton, etal. did not produce his 3β-O-substituted-Δ⁵ -enimide from a17β-cyano-17α-hydroxy steroid (II) but rather produced it by a differentprocess from a 17(20)-unsaturated steroid.

R. B. Boar, et al., in J.C.S. Perkin I 1242 (1975) reported a3β-acetoxy-Δ⁵ -20-acetyl enimide, starting with a pregnenolonederivative. While these compounds are somewhat similar to the enimide(III) of the present invention, the prior art compounds disclose anester at the 17α position. The present process has the flexibility toproduce the enimide (III) where the C₁₇ hydroxyl group is protected withan ether not an ester (acetate). The ester protecting group of the priorart processes has the disadvantage of being difficult to remove,whereas, the C₁₇ ethers of the present invention do not have thatproblem. Again, the enimide produced by Boar, et al. was produced from adifferent starting material by a process different than that of thepresent invention, i.e. the transformation of the 17-protected17β-cyano-17α-hydroxy steroid (II) to the enimide (III).

The Δ²⁰ -enamide acylate (IV) is known where the steroid A-ring is3β-hydroxy-Δ⁵ (C). Boar et al. produced their Δ²⁰ -enamide acylate fromthe corresponding 3β-acetyl-Δ⁵ -enimide by reaction with acetic acidcontaining trichloroacetic acid. See R. B. Boar, et al., J.C.S. Perkin I1242 (1975). That compound had no substitution in the C-ring. The Δ⁴-3-keto-(A) and Δ¹,4 -3-keto-(B)-Δ²⁰ -enamide acylates of the presentinventions are easier to convert to the commercial corticoid productsthan is the compound dislosed by Boar, et al.

The Δ²⁰ -enamide (V) is a tautomer of the enimide (III). Boar, supra,disclosed a Δ²⁰ -enamide. That compound, compound IV on p. 1243, differsfrom the Δ²⁰ -enamide (V) in that at C₁₇ the group is an ester, whereas,the Δ²⁰ -enamides (V) must have an ether or hydroxy group at C₁₇. It hasbeen found that use of ethers at C₁₇ (--OZ) permit the reaction of the17-protected-17β-cyano-17α-hydroxy steroid (II) with Grignard reagentsto produce the enimide (III) and further the Δ²⁰ -enamide (V). D. H. R.Barton, et al., J.C.S. Chem. Comm. 774 (1981) also discloses a Δ²⁰-enamide 17-acetate, see compound (5). That compound further differsfrom the Δ²⁰ -enamides (V) of the present invention in that thesubstituent on the enamide nitrogen atom is an aldehyde (a formyl group)in Barton but is an acyl group in the present invention.

Boar, supra, discloses the transformation of an enimide-17-ester to aΔ¹⁶ -progesterone. The process of the present invention involves thetransformation of an enimide-17α-ether (III, Z is not a hydrogen atom)or its tautomer, a Δ²⁰ -enamide-17-ether (V) to a Δ²⁰ -enamide 17-ester(IV), by an ether to ester exchange followed by hydrolysis to give aprogesterone 17-acylate (VI). Boar discloses the hydrolysis of anenimide 17-acetate to a 20-keto-17-acetate (VI). The process of thepresent invention does not include the enamide 17-acetate of Boar or theprocess of its formation.

The oxazoline (IX), structure type, is known, see Great Britain Pat. No.2,086,907A and J.C.S. Chem. Comm. 774 (1981). D. H. R. Barton, et al. inJ.C.S. Chem. Comm. 774 (1981) transformed a Δ¹⁷(20) -20-amide to theoxazoline by reactions with a peracid whereas the process of the presentinvention starts with an enimide (III). Barton, et al. proposed amechanism for his reaction involving an 17,20-epoxide and a17α-hydroxy-20-enimide. However, none of the intermediates wereisolated, identified or the mechanism proved. The21-bromo-20-formaldimine 17-acetate (XVI) is disclosed by Barton, supra.

The 21-halo-Δ²⁰ -enamides (XX) are not known. The unhalogenated Δ²⁰-enamide 17-acylate is known where the steroid A-ring is of the3β-hydroxy-Δ⁵ series, see Boar and Barton supra. With ether substitutionat C-17, the unhalogenated Δ²⁰ -enamide 17-ethers are unknown regardlessof the substitution in the A-ring.

By the process of the present invention the Δ²⁰ -enamide (V) isconverted into the corresponding 21-halo enimide (XV) in a one-stepprocess. D. M. R. Barton, et al., JCS Chem. Comm., 774 (1981) disclosedthe transformation of a Δ²⁰ -enamide (5), where the nitrogen wassubstituted with a formamide to the 21-bromo enimide (6) where bothcontain the 17-acetate.

The 21-halo enimide (XV) can be transformed to the 17α-hydroxy-21-bromosteroid (XIII) directly or indirectly via the 21-halo-Δ²⁰ -enamide (XX).Barton, supra, disclosed transformation of the 21-bromo steroid (7) tothe 21-bromo-20-keto steroid (8) in which the ester at C-17 was notlost. The process of the present invention produces the free17α-hydroxy-21-bromo-20-keto steroid (XIII).

BRIEF DESCRIPTION OF THE INVENTION

Disclosed are 17β-cyano-17α-hydroxy (IB), 17-protected-17β-cyano (IIB),enimide (II A-C), Δ²⁰ -enamide (V A-C), 21-haloenimide (XV A-C),21-halo-Δ²⁰ -enamide (XX A-C), Δ²⁰ -enamide acylate (IV A,B),17β-cyano-17α-hydroxy (IC) and 17β-cyano-17α-hydroxy (IA') steroids.

Disclosed is a process for the preparation of a C₃ protected form of anenimide (III A-C) which comprises (1) contacting a C₃ protected form ofa 17-protected-17β-cyano-17α-hydroxy steroid (II A-C) with a methylatingagent and contacting the product of step (1) with an acylating orsilating agent.

Also disclosed is a process for the preparation of a C₃ protected formof a Δ²⁰ -enamide acylate (IV A-C) which comprises contacting a steroidselected from the group consisting of a C₃ protected form of an enimide(III A-C) or a C₃ protected form of a Δ²⁰ -enamide (V A-C) with acarboxylic acid of the formula R₁₇ COOH and an anhydride of the formula(R₁₇ CO)₂ O where R₁₇ is a hydrogen atom alkyl of 1 thru 5 carbon atoms,phenyl substituted with zero thru 2 chlorine atoms, trichloromethyl ortrifluoromethyl groups.

Further disclosed is a process for the preparation of a C₃ protectedform of a Δ²⁰ -enamide (V A-C) which comprises contacting a C₃-protected form of an enimide (III A-C) with an acid or base.

Also disclosed is a process for the preparation of a C₃ protected formof an oxazoline (IX A-C) which comprises contacting a steroid selectedfrom the group consisting of a C₃ protected form of an enimide (III A-C)or a C₃ protected form of a Δ²⁰ -enamide (V A-C) with an acid in anorganic solvent or mixtures thereof.

Further disclosed is a process for the preparation of a steroid selectedfrom the group consisting of a C₃ protected form of a 21-halo enimide(XV A-C) and a C₃ protected form of a 21-halo-Δ²⁰ -enamide (XX A-C)which comprises contacting a C₃ protected form of a Δ²⁰ -enamide (V A-C)with a halogenating agent.

Further disclosed is a process for preparing a C₃ protected form of a17α-hydroxy steroid (XIII A-C) which comprises (1) contacting a steroidselected from the group consisting of a C₃ protected form of a 21-haloenimide (XV A-C) or a C₃ protected 21-halo-Δ²⁰ -enamide (XXA-C) with anaqueous acid.

DETAILED DESCRIPTION OF THE INVENTION

The 17-keto steroid starting materials are well known to those skilledin the art or can readily be prepared from known compounds by methodswill known to those skilled in the art. These include Δ⁴ -3-keto (A),Δ¹,4 -3-keto (B) and 3β-hydroxy-Δ⁵ (C) steroids, see Chart G. The17-keto starting materials can be substituted at C₆, C₉, C₁₁ and/or C₁₆,with R₆, R₉, R₁₁ and R₁₆ as defined infra.

The A-ring of the 17-keto starting material does not have to beprotected to form the 17β-cyano-17α-hydroxy steroid (I). However, duringthe methylation reaction of transforming the17-protected-17β-cyano-17α-hydroxy steroid (II) to the enimide (III) theA-ring must be protected.

For the Δ⁴ -3-keto steroids (A) the C₃ ketone is protected as the enolether (Aa), ketal (Ab), or enamine (Ac) as is well known in the art, seeChart H. The preferred enol ether (Aa) is the methyl or ethyl ether. Thepreferred ketal (Ab) is the ethylene ketal. The preferred enamines areselected from the group consisting of pyrrolidine, morpholine anddiethylamino amines. The enol ethers (a) are prepared by methods wellknown in the art, See J. Org. Chem. 26, 3925 (1961), Steroid Reactions,Edited by Carl Djerassi, Holden-Day, San Francisco, 1962, p. 42-45, andU.S. Pat. No. 3,516,991 (Preparation 1). The ketals (b) are alsoprepared by well known methods, see Steroid Reactions, supra,, p. 11-14.The 3-enamines (c) are also prepared by methods well known in the art,see U.S. Pat. No. 3,629,298 and Steroid Reactions, supra, p. 49-53.

The Δ¹,4 -3-keto steroids (B) are protected by reacting the17-protected-17β-cyano-17α-hydroxy steroid (II) with a strong base suchas LDA (lithium diisopropyl amide) to form an enolate represented byformula (Ba). The enolate is then methylated and acylated or silated toform the enimide (III). In the process the 3-enolate is also acylated orsilated to give the 3-acylate or 3-silyl derivative of (Ba). In asubsequent workup and hydrolysis the A-ring enolate reforms the Δ¹,4-3-keto (B) A-ring functionality.

The 3-hydroxy steroid (C) should have the 3β-hydroxyl group protected asthe ether (Ca), see Chart H.

The C₃ protected forms (Aa, Ab and Ac) of the Δ⁴ -3-keto steroids (A),the C₃ protected forms (Ba) of the Δ¹,4 -3-keto steroids (B) and the C₃protected forms (Ca and Cb) of the 3β-hydroxy steroids (C) areconsidered equivalent to the non-protected or free form (A, B and C)respectively since the C₃ protecting groups are readily removable toconvert the C₃ protected forms (Aa, Ab, Ac, Ba and Ca) to the free orunprotected forms (A, B and C) respectively. In order to remove the C₃protecting group from the Δ⁴ -3-keto steroids (A), Δ¹,4 -3-keto steroids(B) and 3β-hydroxy steroids (C) the reaction conditions would generallyalso remove the C₁₇ protecting group (Z) which is undesirable.Therefore, the C₃ protecting group remains during subsequent reactionsnot because it is needed per se but rather so as not to remove the (Z)protecting group. The C₃ and C₁₇ protecting groups can readily beremoved, if desired, from the intermediates producing17α-hydroxy-free-A-ring steroids.

The 17-keto steroid starting material is reacted with potassium cyanideand 2-cyano-2-hydroxypropane (acetone cyanohydrin) in an alcoholicsolvent such as aqueous methanol to give the desired17β-cyano-17α-hydroxy steroid (I) with high yields and stereospecificityas is known in the art. The reaction may be heated to 30°-50° ifdesired.

Before protecting the 17α-hydroxy group of the cyanohydrin (I), it ispreferred that the C₃ function of the Δ⁴ -3-keto (A), Δ¹,4 -3-keto (B)or 3β-hydroxy-Δ⁵ (C) steroids be protected as discussed supra althoughthe 17α-hydroxy group may be protected first. 17β-Cyano-17α-hydroxysteroids (I) are known where the 17α-hydroxy group is protected as anether. See, Steroids 37, 362 (1981) on p 362 for the TMS ether; J. Am.Chem. Soc. 81, 5725 (1959) on p 5726 formula III as the THP ether;Tetra. Lett. 22, 2005 (1971) on p 2007 formula 1X as the TMS ether andJapanese Pat. No. 7,062,296 for the butyl vinyl ether. The preferred17α-protecting group is the ethoxy ethyl ether. Other suitable groupsinclude THP, TMS, methoxymethyl, and butoxy ethyl ethers. Theappropriate form of the 17β-cyano-17α-hydroxy steroid (I) is reactedwith a reagent to form the desired ether protecting group (Z) such asethoxy ethyl ether (EEE) using an acid catalyst such as pyridinehydrochloride, p-TSA, or in an inert solvent. Suitable solvents includetoluene, SSB, cyclohexane, methylene chloride.

The enimide (III) and the Δ²⁰ -enamide (V) are tautomers. The17-protected-17β-cyano-17α-hydroxy steroid (II) can be converted to boththe enimide (III) and the Δ²⁰ -enamide (V). The17-protected-17β-cyano-17α-hydroxy steroid (II) is converted to theenimide (III) by first reaction with a methylating agent. Addition ofthe methylating agent to the protected cyanohydrin (II) gives anintermediate imine which can be isolated, but it is preferred to acylateor silate the imine anion in situ by addition of an acylating orsilating agent. The acylating agents are selected from the groupconsisting of acyl halides and acyl anhydrides of the formulas R₂₀ J,(R₂₀)₂ O, or R₂₀ "J. Suitable solvents for this reaction include etherssuch as THF. The reaction is performed in the temperature range of about-30° to about 100°. Silating agents include J-Si(CH₃)₃ and J-Si(CH₃)₂C(CH₃)₃.

Some methylating agents have greater Lewis acid properties or formbetter Lewis acids after methylation than other methylating agents. Forexample, methyl Grignard is a better Lewis acid than methyl lithium.Methylating agents such as methyl Grignard having sufficient Lewisacidity transform the initially formed enimide (III) to its tautomericform the Δ²⁰ -enamide (V). Thus, with the methylating agents which areLewis acids, such as methyl magnesium chloride the ratio of tautomericproducts, the enimide (III) and Δ²⁰ -enamide (V) is time dependent. Atshort time periods the predominate product is the enimide (III). Withtime there is a decrease in the amount of enimide (III) and increase theamount of Δ²⁰ -enamide (V) to the point where predominately the Δ²⁰-enamide (V) is present. Methylating agents which are poor Lewis acidsinclude, for example, methyl lithium. The17-protected-17β-cyano-17α-hydroxy steroid (II) is transformed to theenimide (III) if the methylating agent is methyl lithium and the imineanion formed is acylated or silated. Methylating agents which are orproduce Lewis acids include Grignard reagents, for example, methylmagnesium bromide, chloride and iodide. For example, if the methylatingagent is methyl magnesium bromide and the acylating agent is aceticanhydride, during the methylation/acylation step of transforming the17-protected-17β-cyano-17α-hydroxy steroid (II) to the enimide (III) themethyl magnesium bromide is transformed to magnesium bromoacetate whichis a (Lewis) acid and therefore the enimide (III) which is initiallyproduced is transformed to the Δ²⁰ -enamide (V) without addition ofanother acid, see Example 7. If it is desired to isolate the enimide(III) the preferred methylating agent utilized in the methylationreaction is one that in situ will not be transformed to a Lewis acid.Methyl lithium is a methylating agent operable in effectuating themethylation reaction but will not form a Lewis acid and will permitisolation of the enimide (III), see Examples 5 and 31. The preferredmethylating reagent is methyl lithium.

The enimide (III) is isomerized to its tautomer the Δ²⁰ -enamide (V) byreaction with an acid, or a base. Acids include Lewis acids, andcarboxylic acids including polycarboxylic acids. It is preferred thatthe acid be acetic, propionic, benzoic or citric. The most preferredacid is acetic acid. Bases which are operable include guanidine andamidine bases, preferred are DBU and DBN.

The enimide (III) and Δ²⁰ -enamide (V) are tautomers. Both can betransformed to corresponding Δ²⁰ -enamide 17-ester (IV) by reaction witha carboxylic acid of the formula R₁₇ COOH and a carboxylic acidanhydride of the formula (R₁₇ CO)₂ O in the acid as solvent in thetemperature range of about 0° to about 80° preferably at about 20° toabout 25°. The reaction converts the protecting group "Z" at C-17 to the17-ester (--OCOR₁₇) and with the enimide (III) also the enimide portionis tautomerized to the Δ²⁰ -enamide. It is preferred that R₁₇ is methyl,ethyl or phenyl, more preferably methyl. If R₁₇ is a hydrogen atom,trichloromethyl, trifluoromethyl or an equivalent substituent whichmakes the ester R₁₇ COO-- active, such ester (IV) may be selectivelyremoved with mild base such as bicarbonate in methanol to give the17α-hydroxy-Δ²⁰ -enamide (XVII). Likewise the 21-halo steroid (XI) canbe converted to the 21-halo-17α-hydroxy corticoid (XIII). Alternatively,if R₁₇ is trimethyl silyl or other convenient silyl protecting group,such group may be removed with mild base as above, mild acid or fluorideion producing the desired 17α-hydroxy group in XVII.

The Δ²⁰ -enamide (V) can be transformed to the 17α-hydroxyprogesterone17-ester (VI) by reaction with an appropriate esterifying agent such asan anhydride (R₁₇ CO)₂ O and the corresponding carboxylic acid R₁₇ COOHto produce the enamide acylate (IV) followed by addition of water tohydrolyze the enamide acylate (IV) to the 17α-hydroxyprogesterone17-ester (VI).

The enimide (III) can be readily transformed to a17α-hydroxyprogesterone 17-ester (VI) by reaction with the appropriateesterifying agent such as an anhydride (R₁₇ CO)₂ O or acid halide R₁₇COJ in the corresponding acid, R₁₇ COOH, solvent. Preferred is aceticanhydride in acetic acid followed by water. This in situ acetylationavoids an often difficult separate acylation step on the hinderedtertiary 17α-hydroxy group, see U.S. Pat. No. 4,154,748. If one were tostart with androstenedione as the 17-ketone and perform the process ofthe present invention using acetic anhydride/acetic acid in convertingthe enimide (III) or Δ²⁰ -enamide (V) to the Δ²⁰ -enamide acylate (IV),one would obtain on hydrolysis 17α-hydroxyprogesterone 17-acetate (VI'A)as the 17α-hydroxyprogesterone 17-ester (VI), see Chart B. The17α-hydroxyprogesterone 17-acetate (VI'A) can be transformed to17α-hydroxy-6-methyleneprogesterone 17-acetate (VII) by the process ofU.S. Pat. No. 3,642,840, Example 11 which can be transformed to17α-hydroxy-6α-methylprogesterone 17-acetate (VIII) which ismedroxyprogesterone by the process of U.S. Pat. No. 3,679,715, Example1.

Alternatively, by starting with 6α-methylandrost-4-ene-3,17-dione (U.S.Pat. No. 3,166,551, Example 8) as the 17-keto steroid and performing theprocess of the present invention using acetic anhydride/acetic acid asthe acetylating agent, 17α-hydroxy-6α-methylprogesterone 17-acetate(VIII) is obtained directly.

Just as the tautomers, the enimide (III) and Δ²⁰ -enamide (V) can bothbe transformed to the corresponding Δ²⁰ -enamide 17-ester (IV), likewisethey both can readily be converted to the oxazoline (IX) by contactingthe tautomer with an acid in an organic solvent. Mineral, Lewis, ororganic acids are suitable. This would include sulfuric, hydrochloric,phosphoric and equivalent inorganic acids. Organic acids such as p-TSAand carboxylic (R₁₇ COOH) and dicarboxylic acids such as oxalic acidalso are operable and are preferred. Suitable organic solvents include,for example, toluene, methylene chloride, ethyl acetate, methanol,ethanol, THF, diethyl ether, and mixtures thereof. The enimide (III) orΔ²⁰ -enamide (V) is contacted with the acid in the suitable organicsolvent in a temperature range of about 20° to about 60°. The reactionmixture can be heated to the reflux temperature of the particularsolvent used. The reaction is monitored by TLC and when complete theoxazoline (IX) is isolated by means well known to those skilled in theart or can be halogenated without isolation.

The oxazoline (IX) is a very useful intermediate in the production ofcorticoid diesters (XII), see Chart C. The oxazoline (IX) is halogenatedto produce the halo-oxazoline (X) according to the procedure set forthin J.C.S. Chem. Comm. 774 (1981). The halooxazoline (X) is then readilyconverted by hydrolysis to the 21-halo steroid (XI) which is readilytransformed to the pharmacologically useful corticoid diester (XII).Alternatively, the 21-halo enimide (XV) and 21-halo-Δ²⁰ -enamide (XX) isreadily converted into halooxazoline (X) by contacting with an acid inan organic solvent.

The Δ²⁰ -enamide (V) can be readily converted to the corresponding21-halo enimide (XV) by reaction with a halogenating agent selected fromthe group consisting of bromine, pyridine hydrobromide perbromide, NBS,dibromantin and NCS. The 21-halo enimide (XV) can be converted into itstautomer, 21-halo-Δ²⁰ -enamide (XX) under the influence of acid or base.Acids include organic carboxylic acids or polycarboxylic acids either asthe solvent or in suitable organic solvents such as THF, toluene ormethylene chloride. Acids may include Lewis acids such as BF₃ ˜etheratein organic solvent. Bases which are operable include amidine bases.Preferred are DBU and DBN. Under certain conditions the halogenationreaction becomes sufficiently acidic or basic to cause tautomerizationof the 21-halo enimide (XV) to the 21-halo-Δ²⁰ -enamide (XX).

The 21-haloenimide (XV) and/or the 21-halo-Δ²⁰ -enamide (XX) can behydrolyzed under acidic conditions to either the 21-halo steroid (XI) orthe 21-halo-17α-hydroxy corticoid (XIII) depending on the conditionschosen. To prepare the corticoid diester (XII), the 21-haloenimide (XV)or its tautomer 21-halo-Δ²⁰ -enamide (XX) is first hydrolyzed withrelatively high concentrations of aqueous acid with an organiccosolvent. The acids include mineral acids and carboxylic acids such assulfuric, acetic, hydrochloric, etc. Organic cosolvents includemethanol, toluene, methylene chloride. The 21-halo steroid (XI) is thenconverted to the corticoid diester (XII) by treatment with acylate ionin an organic solvent. The preferred conditions are treatment of the21-halo steroid (XI) with potassium acylate in a mixture of DMF andtoluene at 50°-100° for 6-18 hr. Specifically, to prepare the17,21-diacetate (XII) the 21-halo steroid (XI) is treated with potassiumacetate in DMF and toluene at 75° for 18 hr. The corticoid diesters(XII) are important pharmaceuticals, such as betamethasone dipropionateand diflorasone diacetate, and important intermediates such asReichstein's Compound S 17,21-diacetate which is converted tohydrocortisone 17,21-diacetate by fermentation. The corticoid diesters(XII) can be converted to the commercially important 17,21-dihydroxycorticoids by base hydrolysis. For example, hydrocortisone diacetateformula XII where R₁₁ is β-hydroxyl, R₆, R₉ and R₁₆ are hydrogen atomscan be converted to hydrocortisone by treatment with methanolicpotassium carbonate at 20°-25°. Hydrocortisone can be converted tohydrocortisone 21-acetate by reaction with acetic anhydride in pyridineas is well known to those skilled in the art.

To prepare the commercially important corticoid 21-ester (XIV) directlyfrom the 21-halo-Δ²⁰ -enamide (XX) or the 21halo enimide (XV) the21-halo compounds are hydrolyzed with dilute aqueous inorganic mineralacids such as sulfuric, hydrochloric or phosphoric in an organicsolvent. The preferred conditions include treatment of (XV) or (XX) withdilute aqueous sulfuric acid in THF (Example 21) producing the21-halo-17α-hydroxy corticoid (XIII). The 21-halo-17α-hydroxy corticoid(XIII) is converted to the corticoid 21-ester (XIV) by treatment withacylate ion as is well known to those skilled in the art.

DEFINITIONS

The definitions and explanations below are for the terms as usedthroughout the entire patent application including both thespecification and the claims.

All temperatures are in degrees Centigrade.

TLC refers to thin-layer chromatography.

IR refers to infrared spectroscopy.

UV refers to ultraviolet spectroscopy.

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from TMS.

TMS refers to tetramethylsilane.

MS refers to mass spectrometry expressed as m/e or mass/change unit.

When solvent pairs are used, the ratio of solvents used arevolume/volume (v/v).

THF refers to tetrahydrofuran.

DMF refers to dimethylformamide.

SSB refers to an isomeric mixture of hexanes.

p-TSA refers to p-toluenesulfonic acid monohydrate.

Hal is a chlorine, bromine, iodine, atom.

NBS refers to N-bromosuccinimide.

NCS refers to N-chlorosuccinimide.

TMS refers to tetramethylsilyl

THP refers to tetrahydropyronyl

EEE refers to ethoxy ethyl ether (--O--CH₂ CH₂ OCH₂ CH₃).

DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

DBN refers to 1,6-diazabicyclo[3,4,0]non-5-ene.

LDA refers to lithium diisopropyl amide.

MEM refers to 2-methoxyethoxymethyl (CH₃ OCH₂ CH₂ OCH₂ O--).

Androstenedione refers to androst-4-ene-3,17-dione.

When the term "alkyl of ₋₋₋₋ thru ₋₋₋₋ carbon atoms" is used, it meansand includes isomers thereof where such exist.

R refers to alkyl 1 thru 5 carbon atoms or a hydrogen atom with theproviso that the R's can be the same or different.

R_(a) is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.

R_(g) is R_(a), a hydrogen atom or phenyl.

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac); the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom.

R₆ is a hydrogen or fluorine atom or methyl group.

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom.

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond.

R₁₆ is a hydrogen atom or methyl group.

R₁₇ is a hydrogen atom alkyl of 1 thru 5 carbon atoms, phenylsubstituted with zero thru 2 chlorine atoms, trichloromethyl ortrifluoromethyl groups.

R₁₇ ' is a hydrogen atom or trifluoromethyl group.

R₂₀ is --OC--R₂₀ ' or --R₂₀ ".

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups.

R₂₀ " is --Si(CH₃)₃ or --Si(CH₃)₂ C(CH₃)₃.

R₂₁ is alkyl of 1 thru 5 carbon atoms or phenyl.

R₁₀₀ is alkyl of 1 thru 3 carbon atoms.

R₁₀₁ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.

R₁₀₂ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.

R₁₀₃ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.

R₁₀₄ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.

R₁₀₅ is a hydrogen atom or alkyl or 1 thru 3 carbon atoms.

R₁₀₆ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a secondary amine selected from the group consisting ofpiperidine, pyrrolidine or morpholine with the proviso that R₁₀₆ andR₁₀₇ combined cannot have more than 14 carbon atoms; R₁₀₆ and R₁₀₇ canbe combined to form a secondary cyclic amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.

R₁₀₇ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 2 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a secondary amine selected from the group consisting ofpiperidine, pyrrolidine or morpholine with the proviso that R₁₀₆ andR₁₀₇ combined cannot have more than 14 carbon atoms; R₁₀₆ and R₁₀₇ canbe combined to form a secondary cyclic amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.

J is a chlorine, bromine or iodine atom.

M is a lithium sodium potassium magnesium or calcium atom.

Q refers to a hydrogen atom, or alkyl of 1 thru 5 carbon atoms.

W is a TMS, THP, or EEE group.

X refers to a hydrogen atom or nothing.

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group.

Z' is a hydrogen atom or Z.

˜ indicates that the attached atom or group can be in either the α or βconfigurations.

. . . is a single or double bond.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention tothe fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

EXAMPLE 1 17β-Cyano-17α-hydroxyandrost-4-en-3-one (IA)

Acetone cyanohydrin (82 ml), potassium cyanide (1 gm) and water (2 ml)are added to a slurry of androst-4-en-3,17-dione (0.80 g) in methanol(400 ml) and water (40 ml) at 35°. The reaction becomes homogeneous andon continued stirring a heavy slurry develops. After 3 hours, 120 ml ofwater is added dropwise, and the slurry allowed to stir overnight at20°-25°. The slurry is then cooled in an ice bath, filtered, and thesolids washed with methanol/water (1/1). The solvents are dried underreduced pressure to give 70.4 g of the title compound. An additional13.17 g of product is isolated from the mother liquor on partialevaporation, m.p.=159°-160.5°; [α]^(D) (c=1, CHCl₃)=+145.9°; MS=313,298, 286, 245 and 124 m/e; NMR (CDCl₃)=1.00, 1.20, 3.5 and 5.72 δ

EXAMPLE 2 17β-Cyano-17α-hydroxyandrosta-4,9(11)-dien-3-one (IA)

Acetone cyanohydrin (5 ml) and sufficient potassium cyanide to adjustthe pH to 9.9 is added to a slurry of androst-4,9(11)-dien-3,17-dione(0,5 g), methanol (40 ml) and water (2.5 g) at 40°. The reaction becomeshomogeneous followed by precipitation of the product. After 3.5 hours,water (7.5 ml) is added dropwise and the reaction is allowed slowly tostir at 20°-25° overnight. The slurry is cooled on in ice bath,filtered, the solids washed with methanol/water (1/1) and dried underreduced pressure to give the title compound (4.54 g); [α]^(D) (c=1,CHCl₃)=+118°; MS=311, 296 and 284 m/e; NMR (CDCl₃)=0.97, 1.37, 2.9, 5.5and 5.70 δ

EXAMPLE 3 17β-Cyano-17α-hydroxyandrost-5-en-3-ethylidine ketal (IAb)

p-TSA (100 mg) is added to a mixture of17β-cyano-17α-hydroxyandrost-4-en-3-one (IA, Example 1, 5 g) inmethylene chloride (50 ml), ethylene glycol (5 ml) andtrimethylorthoformate (2.5 ml). The resulting mixture is stirred 2 hoursat 20°-25°. The reaction mixture is concentrated to approximately 20 mlat atmospheric pressure. Triethylamine (0.2 ml) is added, the mixtureextracted with phosphate buffer (pH 7) and the organic phaseconcentrated to a solid. The solid is crystallized from methanol to givethe title compound (5.1 g); m.p.=229.5°-230.5°; [α]^(D) (c=1,CHCl₃)=+4.2°; MS=357, 342, 330 and 302 m/e; NMR (CDCl₃)=0.93; 1.10, 3.3,3.97 and 5.3 δ

EXAMPLE 4 17β-Cyano-17α-(α-ethoxyethyl)-etherandrost-5-en-3-ethylidineketal (IIAb)

A mixture of 17β-cyano-17α-hydroxyandrost-5-en-3-ethylidine ketal (IAb,Example 3, 3.57 g) in methylene chloride (10 ml) containing ethyl vinylether (2 ml) and pyridine hydrochloride (100 mg) is heated in a sealedbottle at 40° for 2.5 hours and at 40° for 4 hours. Triethylamine (0.2ml) is added and the reaction washed with phosphate buffer (pH 7), waterand then dried over sodium sulfate, filtered and the filtrateconcentrated under reduced pressure to give the title compound (4.61 g)as an oily mixture of diastereomers; NMR (CDCl₃)=0.98, 1.04, 3.5, 3.94,5.0 and 5.2 δ

EXAMPLE 517α-(α-ethoxyethyl)-ether-20-acetyliminopregn-5-en-3-ethylidine ketal(IIIAb)

Methyl lithium (1.5M, 1.2 ml) is added to a mixture of17β-cyano-17α-(α-ethoxy ethyl)-ether-androst-5-en-3-ethylidine (IIAb,Example 4, 550 mg) and toluene (3.5 ml) at 0°. After 2.5 hours at 0° thereaction is quenched by adding acetic anhydride (1 ml) and toluene (1ml) resulting in a stirrable gel. Aqueous phosphate buffer (pH 7) isadded, the phases are separated and the the lower aqueous phase isbackwashed with ethyl acetate. The combined organic phases arebackwashed with sodium bicarbonate (5%), phosphate buffer, dried oversodium sulfate and concentrated to give the title compound (643 ml) asan oil; NMR (CDCl₃)=0.71, 1.02, 1.92, 2.00, 2.12, 3.4, 3.93, 4.7 and 5.3δ; MS=487, 415 and 297 m/e

EXAMPLE 617α-(α-ethoxyethyl)-ether-20-acetylaminopregna-5,20-dien-3-ethylidineketal (VAb)

17α-(α-ethoxyethyl)-ether-20-acetylaminopregna-5-en-3-ethylidine ketal(IIIAb, Example 5, 3 mM) is stirred in glacial acetic acid (2 ml) for1.5 hour at 20°-25°. Toluene is added and the organic diluents removedunder reduced pressure. Additional toluene is added and the mixturewashed with sodium bicarbonate (5%), phosphate buffer and the organicphase is dried over sodium sulfate and concentrated under reducedpressure to give the title compound (1.7 g) as an oil, NMR (CDCl₃)=0.69,1.02, 2.03, 3.4, 3.94, 4.6, 4.82, 4.97, 5.3, 5.84, 6.03 and 6.8 δ

EXAMPLE 717α-(α-ethoxyethyl)-ether-20-acetylaminopregna-5,20-dien-3-ethylidineketal (VAb)

Methyl magnesium bromide in ether (2.85M, 7 ml) is added to a mixture of17β-cyano-17α-(α-ethoxyethyl)-etherandrost-5-en-3-ethylidine ketal(IIAb, Example 4, 10 mM) in toluene (25 ml) and the mixture heated at55° for 6 hours in a sealed pressure bottle. The mixture is thendissolved in THF (10 ml) and is added to toluene (20 ml) containingacetic anhydride (3 ml) which had been previously cooled to 0°. Thismixture is allowed to warm to 25° during a 1/2 hour stirring periodafter which it is extracted with phosphate buffer (twice), dried oversodium sulfate, concentrated to give the title compound as an oil. Thisproduct is spectroscopically and chromatographically identical to theproduct of Example 6.

EXAMPLE 8 17α-Acetoxy-20-acetylaminopregna-5,20-dien-3-ethylidine ketal(IVAb)

17β-Cyano-17α-(α-ethoxy ethyl)-ether androst 5-en-3-ethylidine ketal(VAb, Example 7) is dissolved in glacial acetic acid (10 ml) and aceticanhydride (5 ml) and the mixture stirred for 24 hours at 20°-25°. Thereaction mixture is then added to aqueous phosphate buffer and extractedwith ethyl acetate. The phases are separated and the organic phase iswashed with water, sodium bicarbonate (5%), water again, dried oversodium sulfate and concentrated to give the title compound as an oil;NMR (CDCl₃)=0.73, 1.07, 2.08, 3.97, 5.00, 5.3, 5.8 and 6.6 δ; CMR(CDCl₃)=169.78, 140.23, 138.85, 121.68, 109.35, 104.01, 93.59 and 64.36δ; MS=398 (m+1); IR (CHCl₃)=1730, 1685 cm⁻¹

EXAMPLE 9 17α-Acetoxy-20-acetylaminopregna-5,20-dien-3-ethylidine ketal(IVAb)

Following the general procedure of Example 8 and making noncriticalvariations, but starting with 17α-(α-ethoxyethyl)-ether-20-acetylaminopregn-5-en-3-ethylidine ketal (IIIAb, Example5) the title compound is obtained as an oil identical in all respects tothe product of Example 8.

EXAMPLE 10 17α-Acetoxyprogesterone (VIA)

Acetic acid (1.5 ml) and water (0.5 ml) are added to17α-acetoxy-20-acetylaminopregna-5,20-dien-3-ethylidine ketal (IVAb,Example 8, 0.5 mM) in acetic acid (0.66 ml) and acetic anhydride (0.34ml). The reaction mixture is heated at 55° for approximately 18 hours.TLC (ethyl acetate/toluene:3/7) shows the hydrolysis to be complete toapproximately a 90/10 mixture of 17α-acetoxyprogesterone and17α-hydroxyprogesterone. Acetic anhydride (0.75 ml) and p-TSA (30 mg)are added and heating continued for 2 hours at 50°. Water (0.3 ml) isadded and the heating is continued at 50° for 7.5 hours. Water (2 ml) isthen added resulting in a precipitate which is filtered and dried togive the title compound.

EXAMPLE 1117R,2'-Methyl-4'-methylenespiro-3-ethylenedioxyandrost-5-en-17,5'(4'H)-oxazole(IXAb)

Acetic acid (5 ml) and acetic anhydride (0.4 ml) are added to17α-(α-ethoxyethyl)-ether-20-acetylaminopregn-5-en-3-ethylidine ketal(IIIAb, Example 5, 10 mM) and the mixture heated to 55°. After 1 hour ofheating at 55°, additional acetic acid (5 ml) and acetic anhydride (0.4ml) are added and the heating continued for an additional 2.5 hours. Thereaction mixture is cooled, the solid filtered, washed with diethylether and dried to give the title compound (1.45 g), m.p.=199°-209°; NMR(CDCl₃)=0.81, 1.03, 2.04, 3.86, 4.65 and 5.30 δ; MS (CI)=398 (M+1)

EXAMPLE 1217R,2'-Methyl-4'-methylenespiro-3-ethylenedioxyandrost-5-en-17,5'(4'H)-oxazole(IXAb)

Methanol (2 ml) and p-TSA.H₂ O (2 ml) is added to17α-(α-ethoxyethyl)-ether-20-acetylaminopregn-5,20-dien-3-ethylidineketal (VAb, Example 6, 200 ml) and the mixture heated to 70° for 40minutes. Analysis by TLC and NMR shows that the product is mostly thetitle compound along with small amounts of 3-methyl enol ether andΔ4-3-keto analogues.

EXAMPLE 1317R,2'-Methyl-4'-bromomethylenespiro-3-ethylenedioxyandrost-5-en-17,5'(4'H)-oxazole(XAb)

Pyridium bromide perbromide (3 ml) is added to17R,2'-methyl-4'-methylenespiro-3-ethylenedioxyandrost-5-en-17,5'(4'H)-oxazole(IXAb, Example 11, 50 ml) in methylene chloride (1 ml) and pyridine(0.05 ml) at 0°. TLC shows a single less polar product. A few drops ofsodium bisulfite (1M) and acetic acid are added. The phases areseparated and the organic phase is washed with water, dried over sodiumsulfate, and concentrated to give the title compound, NMR (CDCl₃)=0.92,1.03, 2.17, 3.93, 5.27 and 5.33 δ; MS (CI,CH₄)=476, 478 (M+1), 396

EXAMPLE 14 21-Bromo-17α-acetoxyprogesterone (XIA)

17R,2'-Methyl-4'-bromomethylenespiro-3-ethylenedioxyandrost-5en-17,5'(4'H)-oxazole(XAb, Example 13). The product from Example 13 is dissolved in asolution of acetic acid (0.75 ml) and water (0.25 ml) and heatedovernight at about 105° in a sealed vial. The reaction mixture is thenadded dropwise to a solution of phosphate buffer (pH 7) giving the titlecompound, NMR (CDCl₃)=0.72, 1.17, 2.10, 3.90 and 5.67 δ

EXAMPLE 1521-Bromo-17α-(α-ethoxyethyl)-ether-20-acetyliminopregna-5-en-3-ethylidineketal (XVAb)

Pyridinium hydrobromide perbromide (0.29 g) is added to 17α-(α-ethoxyethyl)-ether-20-acetylaminopregna-5,20-dien-3-ethylidine ketal (VAb,Example 6, 411 mg) in a mixture of methylene chloride (3 ml), methanol(0.75 ml), water (0.12 ml) and triethylamine (0.26 ml) at 0°. Thereaction is complete after about 5 minutes. Methylene chloride and waterare added, the phases separated, the organic phase is dried over sodiumsulfate and concentrated to give the title compound, NMR (CDCl₃)=0.77,0.83, 1.03, 2.27, 2.29, 3.9 and 5.27 δ; MS (CI)=566 and 568 (m+1) and550.

EXAMPLE 16 21-Bromo-17α-acetoxy-20-acetylaminopregn-5-en-3-ethylidineketal (XVIAb)

Pyridinium hydrobromide perbromide (100 ml) is added to17α-acetoxy-20-acetylaminopregn-5,20-diene-3-ethylidine ketal (IVAb,Example 8, 140 ml), and the mixture is stirred for 15 minutes at 0°.Phosphate buffer (pH 7) is added, the phases are separated and theorganic phase is washed with sodium bicarbonate (5%), water, dried oversodium sulfate and concentrated to an oil. The oil is chromatographedover silica gel (10 gm) eluting with acetone/methylene chloride: 5/95,the appropriate fractions are pooled and concentrated to give the titlecompound; NMR (CDCl₃)=0.82, 1.03, 2.07, 2.30, 3.9, and 5.28 δ; MS(CI)=536 and 538 (m+1).

EXAMPLE 1721-Bromo-17α-acetoxy-20-acetylaminopregna-5,20-dien-3-ethylidine ketal(XXIAb)

DBW (0.5 ml) is added to21-Bromo-17α-acetoxy-20-acetylaminopregn-5-en-3-ethylidine ketal (XVIAb,Example 16, 3.16 g) and toluene (8.5 ml). After 1/2 hour thetautomerization is complete. The reaction mixture is washed withphosphate buffer (pH 7), filtered through magnesol, dried over sodiumsulfate and concentrated to give the title compound; NMR (CDCl₃)=0.72,0.77, 1.03, 2.03, 2.06, 3.93, 4.52, 4.80, 5.3, 6.3, 6.4, 6.5 and 7.6 δ

EXAMPLE 18 21-Bromo-17α-acetoxyprogesterone (XIA)

Following the general procedure of Example 19 and making noncriticalvariations, but starting with21-bromo-17α-acetoxy-20-acetylaminopregna-5,20-dien-3-ethylidine ketal(XXIAb, Example 17), the title compound is obtained.

EXAMPLE 19 21-Bromo-17α-acetoxyprogesterone (XIA)

Acetic acid (1.5 ml) and water (0.5 ml) are added to21-bromo-17α-acetoxy-20-acetylamino-pregn-5-en-3-ethylidine ketal(XVIAb, Example 16, 38 mg). The mixture is heated in a sealed vial at108° for one hour. Toluene is added to the cooled reaction mixture, thephases separated, the organic phase washed with water, dried over sodiumsulfate and concentrated under reduced pressure to give the titlecompound, NMR (CDCl₃)=0.73, 1.20, 2.10, 3.93, and 5.67 δ

EXAMPLE 20 17α,21-Dihydroxypregn-4-en-3,20-dione 17,21-diacetate (XIIA)

21-Bromo-17α-acetoxyprogesterone (XIA, Example 19, 50 mg) is dissolvedin toluene (0.3 ml) and DMF (0.3 ml) with acetic acid (4 micro liters)and stirred with potassium acetate (19 mg) at 70° in a sealed vial for221/2 hours. Additional toluene is added and the mixture extracted withwater. The organic phase is dried over sodium sulfate and concentratedunder reduced pressure to give the title compound. NMR (CDCl₃) 0.76,1.20, 2.07, 2.13, 4.55, 5.85 and 5.67 δ

EXAMPLE 21 21-Bromo-17α-hydroxyprogesterone (XIIIA)

Sulfuric acid (1N, 1 drop) is added to21-bromo-17α-(α-ethoxyethyl)-ether-20-acetylaminopregn-5-en-3-ethylidineketal (XVAb, Example 15, 50 mg) in THF (0.6 ml) and water (0.2 ml). Thismixture is stirred at 20°-25° for 18 hours and then heated at 60° for17.5 hours to give the title compound, NMR (CDCl₃)=0.73, 1.20, 4.22, and5.70 δ

EXAMPLE 22 21-Bromo-17α-hydroxypregn-5-en-20-one 3-ethylidine ketal(XIIIAb)

Sulfuric acid (1N, 4 drops) is added to21-bromo-17α-(α-ethoxyethyl)-ether-20-acetylaminopregn-5-en-3-ethylidineketal (XVAb, Example 15, 220 mg) in THF (2.5 ml) and water (0.8 ml). Themixture is stirred at 20°-25° for four days. Toluene is added and thereaction mixture washed with buffer (pH 7), dried over sodium sulfateand concentrated to an oil. The oil is chromatographed on a silica gelcolumn diluting with ethyl acetate/hexane: 1/1. The appropriatefractions are pooled and concentrated to give the title compound, NMR(CDCl₃)=0.68, 1.02, 3.91, 4.25, and 5.30 δ; MS (CI)=453, 455 (m+1), 435,437, 373, 357, and 355.

EXAMPLE 23 21-Bromo-17α-hydroxyprogesterone (XIIIA)

21-Bromo-17α-hydroxypregn-5-en-20-on-3-ethylidine ketal (XIIIAb, Example22) is converted to the title compound by heating the reaction mixtureof Example 22 to 60° for about 18 hours instead of stirring at 20°-25°for four days.

EXAMPLE 24 17β-Cyano-3β,11β,17α-trihydroxyandrosta-3,5-diene 3-methylether (IAa)

Pyridine hydrochloride (120 mg), methanol (20 ml) and trimethylorthoformate (3 ml) are added to17β-cyano-11β,17α-dihydroxyandrost-4-en-3-one (IA, Example 25, 6.58 g).The mixture is heated at reflux overnight, cooled to crystallize andreheated for 1.5 hours at 50°-55°. The solid is filtered, washed withbuffer (pH 7), water and dried to give the title compound.

EXAMPLE 25 17β-Cyano-11β,17α-dihydroxyandrost-4-en-3-one (IA)

11β-Hydroxyandrost-4-en-3,17-dione (OA, 5 gms) is added to acetonecyanohydrin (10 ml) and methanol (20 ml). A saturated aqueous solutionof potassium cyanide (5 ml) is added to the steroid mixture. The mixtureis stirred for 21/2 hours during which time the product precipitates.The precipitate is filtered, washed with buffer (pH 7, 25 ml) and waterto give the title compound. This material is purified by chromatographyon silica gel (20% ethyl acetate-chloroform). The appropriate fractionsare pooled and concentrated to give a solid which is recrystallized fromethyl acetate to give the title compound, [α]_(D) ²⁰ +158° (DMSO); IR(KBr)=3500, 3250, 2830--3010, 2220, 1650, cm⁻¹ ; NMR (CDCl₃ /CD₃ OD,1:1)=1.2, 1.47, 4.2, 4.4 and 5.6 δ

EXAMPLE 26 17β-Cyano-11β,17α-dihydroxyandrosta-1,4-dien-3-one (IB)

11β-Hydroxyandrosta-1,4-diene-3,17-dione (OB, 5 gms) is mixed withacetone cyanohydrin (10 ml) and methanol (10 ml). A saturated aqueoussolution of potassium cyanide (10 ml) is added and after 5 minutes, asolution is obtained. The reaction mixture is stirred for one hour,during which time, the product is crystallized. A buffer (ph 7, 50 ml)is added and the slurry filtered. The crystals are washed with buffer,water and dried. The solid material is recrystallized from ethyl acetateto give the title compound [α]_(D) +90° (DMSO); IR (KBr)=3365, 3010,2850, 2220, 1650, 1600, 1570; cm⁻¹ : NMR (CDCl₃ /CD₃ OD, 1:1)=1.23,1.50, 4.18, 4.4, 5.94, 6.18 and 7.33 δ

EXAMPLE 27 17β-Cyano-11β,17α-dihydroxy-6α-methylandrost-4-en-3-one (IA)

11β-Hydroxy-6α-methylandrost-4-ene-3,17-dione (OA, 0.51 gms) is treatedwith acetone cyanohydrin (1 ml) and methanol (1 ml) and saturatedpotassium cyanide (1 ml). After several hours, buffer (pH 7, 5 ml) isadded and the precipitate filtered, washed with water and dried to givea solid. This material is slurried in glacial acetic acid, filtered,washed with acetic acid water and dried to give the title compound[α]_(D) +117° (DMSO); IR (KBr)=3410, 3080, 2840, 2225, 1655 and 1602;cm⁻¹ ; NMR (CDCl₃ /CD₃ OD, 1:1) 1.08, 1.22, 1.47, 4.33, 4.40 and 5.65 δ

EXAMPLE 28 17β-Cyano-11β,17α-dihydroxy-6α-methylandrosta-1,4-dien-3-one(IB)

11β-Hydroxy-6α-methylandrosta-1,4 -diene-3,17-dione (OB, 2.59 gms) isreacted with acetone cyanohydrin (5 ml), methanol (5 ml), and asaturated cyanide solution (5 ml). After three hours of mixing, thereaction is complete as measured by TLC (toluene/ethyl acetate: 20/80).The reaction mixture is diluted with buffer (pH 7, 20 ml), giving asolid which is filtered, washed with water, and dried to give the titlecompound [α]_(D) +85° (DMSO); IR (KBr) 3390, 3300, 3010, 2840, 2230,1650, 1625, 1580, cm⁻¹ ; NMR (CDCl₃ /CD₃ OD, 1:1)=1.1, 1.22, 1.48, 4.40,5.95, 6.2, and 7.30 δ

EXAMPLE 29 17β-Cyano-3β,11β,17α-trihydroxyandrosta-3,5-diene 3-methylether 17α-(α-ethoxyethyl)-ether (IIAa)

17β-Cyano-3β,11β,17α-trihydroxyandrosta-3,5-diene 3-methyl ether (IAa,Example 24, 343 ml) toluene (1 ml), methylene chloride (0.1 ml), ethylvinyl ether (0.6 ml), and pyridine hydrochloride (12 mg) are heatedovernight in a small pressure vessel at 85°. TLC (20% ethylacetate-chloroform) shows the reaction to be complete, containing a lesspolar product. Triethylamine (0.3 ml), buffer (pH 7, 5 ml) and toluene(5 ml) are added and mixed. The layers are separated, the organic phasedried and organic solvents removed to give the title compound.

EXAMPLE 30 11β,17α-Hydroxypregn-4-ene-3,20-dione (XXII)

17β-Cyano-3β,11β,17α-trihydroxyandrosta-3,5-diene 3-methyl ether17α-(α-ethoxyethyl)-ether (IIAa, Example 29), methyl lithium (1.5N, 3ml) are allowed to react at 20°-25° overnight. Water (3 ml), acetic acid(3 ml) and methanol (10 ml) are added. The reaction mixture is taken upin methylene chloride (50 ml) and washed with water (50 ml). The organicphase is separated and washed twice with sulfuric acid (2N, 25 ml)followed by water. The organic solvent is removed and replaced with amixture of ethanol, concentrated hydrochloric acid and water and allowedto stand overnight. Methylene chloride is added, the mixture washed withwater, the organic solvents removed, and the material crystallized fromethyl acetate to give a crystalline product which is identical with11β,17α-dihydroxyprogesterone.

EXAMPLE 31 17α-(α-ethoxyethyl)-ether-20-trifluoroacetylaminopregn-5-ene3-ethylidine ketal (IIIAb)

A solution of17β-cyano-17α-(α-ethoxyethyl)-etherandrost-5-ene-3-ethylidine ketal(IIAb, Example 4, 3.5 mmole) in toluene (12.5 ml) is cooled to 0°.Methyl lithium (1.6M, 2.95 ml) in diethyl ether is added (dropwise) overa period of 4 hours. The reaction is stirred an additional 3 hours at 0°and then quenched at -35° with pyridine (0.76 ml) and trifloroacetichydride (1 ml). The reaction mixture is extracted 3 times with phosphatebuffer (pH 7), the organic layer is dried over sodium sulfate andconcentrated to give the title compound. NMR (CDCl₃) 0.71, 1.01, 1.20,2.05, 2.11, 3.40, 3.90, 4.63 and 5.28 δ

EXAMPLE 3217α-(α-ethoxyethyl)-ether-20-trifluoroacetylaminopregna-5,20-diene-3-ethylidineketal (VAb)

DBU (50 micro liters, 0.3 mmole) is added to17α-(α-ethoxyethyl)-ether-20-trifluoroacetylaminopregna-5-ene-3-ethylidineketal (IIIAb, Example 31, 3.5 mmole) in toluene (10 ml) and stirred at20°-25° for 70 minutes. The mixture is then extracted 3 times withphosphate buffer (pH 7), dried over sodium sulfate and concentrated toan oil. NMR (CDCl₃) 0.70, 1.03, 1.23, 3.47, 3.90, 4.70, 5.04, 5.18,5.29, 5.88 and 6.17 δ

EXAMPLE 3321-Bromo-17α-(α-ethoxyethyl)-ether-20-trifluoroacetyliminopregn-5-en3-ethylidine ketal (XVAb) and21-Bromo-17α-(α-ethoxyethyl)-ether-20-trifluoroacetylaminopregna-5,20-diene3-ethylidine ketal (XXAb)

17α-(α-ethoxyethyl)-ether-20-trifluoroacetylaminopregna-5,20-diene-3-ethylidineketal (VAb, Example 32, 190 mg) is dissolved in methylene chloride (0.5ml) and methanol (0.125 ) with triethylamine (61 micro liters) and water(20 micro liters). The mixture is cooled to 0°. Pyridinium hydrobromideperbromide (0.105 g) is added incremently. The reaction mixture isstirred at 0° for 2-1/5 hours and then extracted with phosphate buffer(pH 7). The organic layer is dried over sodium sulfate and concentratedto give the title compounds. NMR (CDCl₃) 0.71, 0.75, 0.82, 1.03, 1.27,3.43, 3.93, 4.33, 4.70, 5.3, 6.47 and 6.53 δ

EXAMPLE 34 21-Bromo-17α-hydroxyprogesterone (XIIIA) and21-Bromo-17α-trifluoroacetylprogesterone (XIA)

21-Bromo-17α-(α-ethoxyethyl)-ether-20-trifluoroacetyliminopregn-5-en-3-ethylidineketal (XVAb, Example 33) and21-bromo-17α-(α-ethoxyethyl)-ether-20-acetylaminopregna-5,20-diene-3-ethylidineketal (XXAb, Example 33) as an oil (110 ml) containing a mixture of XVAband XXAb is dissolved in THF (1.2 ml) with sulfuric acid (1N, 0.2 ml).The mixture is heated at 54° for 9 hours. The mixture is extracted intoethyl acetate, washed with phosphate buffer (pH 7) to neutrality. Themixture is then concentrated to an oil which as shown by NMR analysiscontains the title compound.

EXAMPLE 35 21-Bromo-17α-hydroxyprogesterone (XIIIA)

21-Bromo-17α-hydroxyprogesterone (XIIIA, Example 34) and21-bromo-17α-trifluoroacetylprogesterone (XIA, Example 34) as an oilcontaining 160 mg of a mixture of XIIIA and XIA is dissolved in methanol(6.0 ml) and water (1 ml) with sodium bicarbonate (172 mg). The mixtureis stirred at 20°-25° for 2 hours. The mixture is extracted withmethylene chloride, the methylene chloride extract is concentrated togive the title compound. NMR (CDCl₃) 0.73, 1.20, 4.09, 4.37 and 5.69 δ.

EXAMPLE 3617R,2'-Methyl-4'-bromomethylenespiro-3-ethylenedioxyandrost-5-en-17,5'(4'H)-oxazole(XAb)

21-Bromo-17α-(α-ethoxyethyl)-ether-20-acetyliminopregn-5-3-ethylidineketal (XVAb, Example 15, 43 mg) is stirred in ethanol (1.5 ml) withboron trifluoride etherate (0.076 mM) at 20°-25° for 3 hr. The reactionis quenched with phosphate buffer (pH 7) and extracted into ethylacetate. NMR and TLC confirmed the identity of the title compound.

EXAMPLE 3717α-(α-ethyoxyethyl)-ether-20-trimethylacetylaminopregna-5,20-diene3-ethylidine ketal (VAb)

A 2:1 mixture of17α-(α-ethoxyethyl)-ether-20-trimethylacetylaminopregna-5,20-diene3-ethylidine ketal (VAb) and17α(α-ethoxyethyl)-ether-20-trimethylacetyl-aminopregn-5-ene3-ethylidine ketal (IIIAb) is dissolved in toluene (5 ml) and THF (1 ml)and stirred with several mg of magnesium bromide under nitrogen at20°-25°. After 16 hr all of (IIIAb) is epimerized to (VAb).

EXAMPLE 38 21-Bromo-17α-hydroxyprogesterone 17-acetate (XIA)

21-Bromo-17α-(α-ethoxyethyl)-ether-20-acetyliminopregn-5-ene3-ethylidine ketal (XVAb), Example 15, 100 mg) is stirred in methanoland sulfuric acid (1N, 0.4 ml) for 19 hr at 20°-25° followed by 46° for3 days giving the title compound.

EXAMPLE 39 21-Bromo-17α-hydroxyprogesterone 17-acetate (XIA)

21-Bromo-17α-(α-ethoxyethyl)-ether-20-acetylaminopregna-5,20-diene3-ethylidine ketal (XXAb, 100 mg) is stirred in acetic acid (1 ml) andwater (0.3 ml) at 60° for 18 hr to give the title compound. ##STR1##

ENUMERATED EMBODIMENTS

The following Enumerated Embodiments further describe the applicant'sinvention.

1. A 17β-cyano-17α-hydroxy steroid of the formula ##STR2## and C₃protected forms thereof where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

. . . is a single or double bond; and

˜ indicates that the attached atom or group can be in either the α or βconfigurations.

2. A 17β-cyano-17α-hydroxy steroid according to Enumerated Embodiment 1where R₉ is nothing, R₁₁ is a hydrogen atom and the C-ring contains aΔ⁹(11) double bond.

3. A 17β-cyano-17α-hydroxy steroid according to Enumerated Embodiment 1which is seleted from the group consisting of17β-cyano-11β,17α-dihydroxyandrosta-1,4-dien-3-one and17β-cyano-11β,17α-dihydroxy-6α-methylandrosta-1,4-diene-3-one.

4. A 17-protected-17β-cyano-17α-hydroxy steroid of the formula ##STR3##and C₃ protected forms thereof where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

. . . is a single or double bond; and

˜indicates that the attached atom or group can be in either the α or βconfigurations.

5. A steroid selected from the group consisting of an enimide of theformula ##STR4## an Δ²⁰ -enamide of the formula ##STR5## and C₃protected forms thereof where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --Si(CH₃)₂ C(CH₃)₃ ;

X refers to hydrogen atom or nothing;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

. . . is a single or double bond; and

˜indicates that the attached atom or group can be in either the a or βconfigurations.

6. A steroid according to Enumerated Embodiment 5 where the Δ⁴ -3-ketosteroid (A) is protected as the ##STR6## where the Δ¹,4 -3-keto steroid(B) is protected as the ##STR7## and where the 3β-hydroxy-Δ⁵ steroid (C)is protected as the ##STR8## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom;

M is a lithium, sodium, potassium, magnesium or calcium atom; and

W is a TMS, THP, or ethoxy ethyl group.

7. An enimide according to Enumerated Embodiment 5 where Z is selectedfrom the group consisting of EEE, THP, TMS, and MEM.

8. An enimide according to Enumerated Embodiment 5 where R₂₀ is selectedfrom the group consisting of acetyl, propionyl, benzoyl, formyl,trichloroacetyl, and trifluoroacetyl.

9. An enimide according to Enumerated Embodiment 5 which is selectedfrom the group consisting of17α-(α-ethoxyethyl)-ether-20-acetylaminopregn-5-en-3-ethylidine ketal,and17α-(α-ethoxyethyl)-ether-20-trifluoroacetylamino-pregn-5-ene-3-ethylidineketal.

10. A process for the preparation of a C₃ protected form of an enimideof the formula ##STR9## which comprises

(1) contacting a C₃ protected form of a17-protected-17β-cyano-17α-hydroxy steroid of the formula ##STR10## witha methylating agent and

(2) contacting the product of step (1) with an acylating or silatingagent where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --SI(CH₃)₂ C(CH₃)₃ ;

X refers to a hydrogen atom or nothing;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

. . . is a single or double bond; and

˜indicates that the attached atom or group can be in either the a or βconfigurations.

11. A process according to Enumerated Embodiment 10 where the Δ⁴ -3-ketosteroid (A) is protected as the ##STR11## where the Δ¹,4 -3-keto steroid(B) is protected as the ##STR12## and where the 3β-hydroxy-Δ⁵ steroid(C) is protected as the ##STR13## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom;

M is lithium, sodium, potassium, magnesium or calcium atom; and

W is a TMS, THP, or ethoxy ethyl group.

12. A process according to Enumerated Embodiment 10 where themethylating agent is selected from the group consisting of methyllithium, methyl magnesium bromide, methyl magnesium chloride and methylmagnesium iodide.

13. A process according to Enumerated Embodiment 10 where the acylatingor silating agent is selected from the group consisting of (R₂₀)₂ O, R₂₀J, or R₂₀ "J where

R₂₀ " is --Si(CH₃)₃ or --Si(CH₃)₂ C(CH₃)₃ and where

J is a chlorine, bromine or iodine atom.

14. A process according to Enumerated Embodiment 13 where the acylatingagent is acetic anhydride or acetyl chloride.

15. A process for the preparation of a C₃ protected form of a Δ²⁰-enamide acylate of the formula ##STR14## which comprises contacting asteroid selected from the group consisting of a C₃ protected form of anenimide of the formula ##STR15## or a C₃ protected form of a Δ²²-enamide of the formula ##STR16## with a carboxylic acid of the formulaR₁₇ COOH and an anhydride of the formula (R₁₇ CO)₂ O where

R₆ is hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₁₇ is a hydrogen atom alkyl of 1 thru 5 carbon atoms, phenylsubstituted with zero thru 2 chlorine, trichloromethyl, trifluoromethyl;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --SI(CH₃)₂ C(CH₃)₃ ;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

X refers to a hydrogen atom or nothing;

. . . is a single or double bond; and

˜indicates that the attached atom or group can be in either the a or βconfigurations.

16. A process according to Enumerated Embodiment 15 where the Δ⁴ -3-ketosteroid (A) is protected as the ##STR17## where the Δ¹,4 -3-keto steroid(B) is protected as the ##STR18## and where the 3β-hydroxy-Δ⁵ steroid(C) is protected as the ##STR19## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom;

M is a lithium, sodium, potassium, magnesium or calcium atom; and

W is a TMS, THP, or ethoxy ethyl group.

17. A process according to Enumerated Embodiment 15 where R₁₇ is methyl,ethyl or phenyl.

18. A process for the preparation of a C₃ protected form of a Δ²⁰-enamide of the formula ##STR20## which comprises contacting a C₃-protected form of an enimide of the formula ##STR21## with an acid orbase where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --SI(CH₃)₂ C(CH₃)₃ ;

X refers to a hydrogen atom or nothing;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

. . . is a single or double bond; and

˜indicates that the attached atom or group can be in either the a or βconfigurations.

19. A process according to Enumerated Embodiment 18 where the Δ⁴ -3-ketosteroid (A) is protected as the ##STR22## where the Δ¹,4 -3-keto steroid(B) is protected as the ##STR23## and where the 3β-hydroxy-Δ⁵ steroid(C) is protected as the ##STR24## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom;

M is a lithium, sodium, potassium, magnesium or calcium atom; and

W is a TMS, THP, or ethoxy ethyl group.

20. A process according to Enumerated Embodiment 18 where the acid is aLewis acid or carboxylic acid.

21. A process according to Enumerated Embodiment 20 where the acid isselected from the group consisting of acetic, propionic, benzoic orcitric acid.

22. A process according to Enumerated Embodiment 18 where the base isselected from the group consisting of DBU, DBN, amidine bases of theformula ##STR25## and quanidine bases of the formula ##STR26## where

R_(a) is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine;

R_(g) is R_(a), a hydrogen atom or phenyl;

R₁₀₁ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine;

R₁₀₂ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine;

R₁₀₃ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine;

R₁₀₄ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine;

R₁₀₆ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a secondary amine selected from the group consisting ofpiperidine, pyrrolidine or morpholine with the proviso that R₁₀₆ andR₁₀₇ combined cannot have more than 14 carbon atoms; R₁₀₆ and R₁₀₇ canbe combined to form a secondary cyclic amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine;

R₁₀₇ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a secondary amine selected from the group consisting ofpiperidine, pyrrolidine or morpholine with the proviso that R₁₀₆ andR₁₀₇ combined cannot have more than 14 carbon atoms; R₁₀₆ and R₁₀₇ canbe combined to form a secondary cyclic amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.

23. A steroid selected from the group consisting of a 21-haloenimide ofthe formula ##STR27## and a 21-halo-Δ²⁰ -enamide of the formula##STR28## and C₃ protected forms thereof where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --SI(CH₃)₂ C(CH₃)₃ ;

X refers to a hydrogen atom or nothing;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

. . . is a single or double bond;

˜indicates that the attached atom or group can be in either the a or βconfigurations; and

Hal is a chlorine, bromine, iodine, atom.

24. A steroid according to Enumerated Embodiment 23 where the Δ⁴ -3-ketosteroid (A) is protected as the ##STR29## where the Δ¹,4 -3-keto steroid(B) is protected as the ##STR30## and where the 3β-hydroxy-Δ⁵ steroid(C) is protected as the ##STR31## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom;

M is a lithium, sodium, potassium, magnesium or calcium atom; and

W is a TMS, THP, or ethoxy ethyl group.

25. A steroid according to Enumerated Embodiment 23 where R₉ is nothing,R₁₁ is a hydrogen atom and the C-ring contains a Δ⁹,11 double bond.

26. A steroid according to Enumerated Embodiment 23 where Z is selectedfrom the group consisting of EEE, THP, TMS, and MEM.

27. A steroid according to Enumerated Embodiment 23 where R₂₀ isselected from the group consisting of acetyl, propionyl, benzoyl,formyl, trichloroacetyl and trifluoroacetyl.

28. A steroid according to Enumerated Embodiment 23 where Hal is abromine atom.

29. A steroid according to Enumerated Embodiment 23 which is selectedfrom the group consisting of21-bromo-17α-(α-ethoxyethyl)-ether-20-acetylamino-pregna-5-en-3-ethylidineketal and21-bromo-17α-(α-ethoxyethyl)-ether-20-acetylamino-pregna-5,20-diene-3-ethylidineketal.

30. A process for the preparation of a C₃ protected form of an oxazolineof the formula ##STR32## which comprises contacting a steroid selectedfrom the group consisting of a C₃ protected form of an enimide of theformula ##STR33## or a C₃ protected form of a Δ²⁰ -enamide of theformula ##STR34## with an acid in an organic solvent or mixtures thereofwhere

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₁₇ is a hydrogen atom alkyl of 1 thru 5 carbon atoms, phenylsubstituted with zero thru 2 chlorine, trichloromethyl, trifluoromethyl;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --SI(CH₃)₂ C(CH₃)₃ ;

X refers to a hydrogen atom or nothing;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

. . . is a single or double bond; and

˜ indicates that the attached atom or group can be in either the a or βconfigurations.

31. A process according to Enumerated Embodiment 30 where the Δ⁴ -3-ketosteroid (A) is protected as the ##STR35## where the Δ¹,4 -3-keto steroid(B) is protected as the ##STR36## and where the 3β-hydroxy-Δ⁵ steroid(C) is protected as the ##STR37## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom;

M is a lithium, sodium, potassium, magnesium or calcium atom; and

W is a TMS, THP, or ethoxy ethyl group.

32. A process according to Enumerated Embodiment 30 where the acid isselected from the group consisting of mineral inorganic acids, organicacids and Lewis acids.

33. A process according to Enumerated Embodiment 32 where the acid isselected from the group consisting of p-TSA, acetic, sulfuric,hydrochloric, phosphoric, formic and benzoic.

34. A process for the preparation of a steroid selected from the groupconsisting of a C₃ protected form of a 21-halo enimide of the formula##STR38## and a C₃ protected form of a 21-halo-Δ²⁰ -enamide of theformula ##STR39## which comprises contacting a C₃ protected form of aΔ²⁰ -enamide of the formula ##STR40## with a halogenating agent where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --SI(CH₃)₂ C(CH₃)₃ ;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

X refers to a hydrogen atom or nothing;

. . . is a single or double bond;

˜ indicates that the attached atom or group can be in either the a or βconfigurations; and

Hal is a chlorine, bromine, iodine, atom.

35. A process according to Enumerated Embodiment 34 where the Δ⁴ -3-ketosteroid (A) is protected as the ##STR41## where the Δ¹,4 -3-keto steroid(B) is protected as the ##STR42## and where the 3β-hydroxy-Δ⁵ steroid(C) is protected as the ##STR43## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom;

M is a lithium, sodium, potassium, magnesium or calcium atom; and

W is a TMS, THP, or ethoxy ethyl group.

36. A process according to Enumerated Embodiment 34 where thehalogenating agent is selected from the group consisting of bromine,NBS, NCS, dibromatin, pyridine hydrobromide.

37. A process for preparing a C₃ protected form of a 17α-hydroxy steroidof the formula ##STR44## which comprises

(1) contacting a steroid selected from the group consisting of a C₃protected form of a 21-halo enimide of the formula ##STR45## or a C₃protected 21-halo-Δ²⁰ -enamide of the formula ##STR46## with an(aqueous) acid where

R₆ is a hydrogen or fluorine atom or methyl group;

R⁹ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --SI(CH₃)₂ C(CH₃)₃ ;

X refers to a hydrogen atom or nothing;

Z is selected from the group consisting of a TMS, THP, methoxymethyl,t-butyl-dimethyl silyl and EEE group;

Hal is a chlorine, bromine, iodine, atom;

. . . is a single or double bond; and

˜ indicates that the attached atom or group can be in either the a or βconfigurations.

38. A process according to Enumerated Embodiment 37 where the Δ⁴ -3-ketosteroid (A) is protected as the ##STR47## where the Δ¹,4 -3-keto steroid(B) is protected as the ##STR48## and where the 3β-hydroxy-Δ⁵ steroid(C) is protected as the ##STR49## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom;

M is a lithium, sodium, potassium, magnesium or calcium atom; and

W is a TMS, THP, or ethoxy ethyl group.

39. A process according to Enumerated Embodiment 37 where the acid is aninorganic mineral acid.

40. A process according to Enumerated Embodiment 37 where the acid issulfuric acid and the solvent is THF.

41. A Δ²⁰ -enamide acylate of the formula ##STR50## and C₃ protectedforms thereof where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

R₁₇ is a hydrogen atom alkyl of 1 thru 5 carbon atoms, phenylsubstituted with zero thru 2 chlorine, trichloromethyl, trifluoromethyl;

R₂₀ is --OC--R₂₀ ' or --R₂₀ ";

R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl, phenyl substituted 0thru 2 chlorine atoms, methyl or nitro groups;

R₂₀ " is --Si(CH₃)₃ or --SI(CH₃)₂ C(CH₃)₃ ;

. . . is a single or double bond; and

˜ indicates that the attached atom or group can be in either the a or βconfigurations.

42. A Δ²⁰ -enamide acylate according to Enumerated Embodiment 41 wherethe Δ⁴ -3-keto steroid (A) is protected as the ##STR51## and where theΔ¹,4 -3-keto steroid (B) is protected as the ##STR52## where

R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that for the ketal(Ab) and the enamine (Ac), the R₃ groups can be connected and whenconnected may be connected by an oxygen or nitrogen atom; and

M is a lithium, sodium, potassium, magnesium or calcium atom.

43. A Δ²⁰ -enamide acylate according to Enumerated Embodiment 41 whereR₉ is nothing, R₁₁ is a hydrogen atom and the C-ring contains a Δ⁹,11double bond.

44. A Δ²⁰ -enamide acylate according to Enumerated Embodiment 41 whereR₂₀ is selected from the group consisting of acetyl, propionyl, benzoyl,formyl, trichloroacetyl and trifluoroacetyl.

45. A Δ²⁰ -enamide acylate according to Enumerated Embodiment 41 whereR₁₇ is selected from the group consisting of methyl, ethyl and phenyl.

46. A Δ²⁰ -enamide acylate according to Enumerated Embodiment 41 whichis 17α-acetoxy-20-acetylaminopregna-5,20-dien-3-ethylidine ketal.

47. A 17β-cyano-17α-hydroxy steroid of the formula ##STR53## and C₃protected forms thereof where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . between C₁₁and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁is a double bond;

R₁₆ is a hydrogen atom or methyl group;

. . . is a single or double bond; and

˜ indicates that the attached atom or group can be in either the a or βconfigurations.

48. A 17β-cyano-17α-hydroxy steroid according to Enumerated Embodiment47 where R₉ is nothing, R₁₁ is hydrogen atom and the C-ring contains aΔ⁹(11) double bond.

49. A 17β-cyano-17α-hydroxy steroid of the formula ##STR54## and C₃protected forms thereof where

R₆ is a hydrogen or fluorine atom or methyl group;

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes the Cring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11-epoxide when R₉ is an oxygen atom;

R₁₆ is a hydrogen atom or methyl group; and

˜ indicates that the attached atom or group can be in either the a or βconfigurations.

50. A 17β-cyano-17α-hydroxy steroid according to Enumerated Embodiment49 which is selected from the group consisting of17β-cyano-11β,∫α-dihydroxy-androst-4-en-3-one and17β-cyano-11β,17α-dihydroxy-6-methylandrost-4-en-3-one.

I claim:
 1. A 17β-cyano-17α-hydroxy steroid of the formula ##STR55## andits C₃ protected enolate ##STR56## where R₆ is a hydrogen or fluorineatom, methyl or methylene group;R₉ is nothing, a hydrogen, fluorine oroxygen atom, which makes the C-ring(a) Δ⁹(11) when R₉ is nothing and (b)9β,11β-epoxide when R₉ is an oxygen atom; R₁₁ is a hydrogen or oxygenatom, two hydrogen atoms, or α- or β-hydroxyl group which makes theC-ring(a) Δ⁹(11) when R₁₁ is a hydrogen atom, (b) 9β,11β-epoxide whenR₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁ is a single bond,and (c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ andR₁₁ is a double bond; R₁₆ is a hydrogen atom or methyl group; . . . is asingle or double bond; ˜ indicates that the attached atom or group canbe in either the α or β configuration; and M is a lithium, sodium,potassium, magnesium or calcium atom.
 2. A 17β-cyano-17α-hydroxy steroidaccording to claim 1 where R₉ is nothing, R₁₁ is a hydrogen atom and theC-ring contains a Δ⁹(11) double bond.
 3. A17-protected-17β-cyano-17α-hydroxy steroid of the formula ##STR57## andits C₃ protected enolate ##STR58## where R₆ is a hydrogen or fluorineatom, methyl or methylene group;R₉ is nothing, a hydrogen, fluorine oroxygen atom, which makes the C ring(a) Δ⁹(11) when R₉ is nothing and (b)9β,11β-epoxide when R₉ is an oxygen atom; R₁₁ is a hydrogen or oxygenatom, two hydrogen atoms, or α- or β-hydroxyl group which makes theC-ring(a) Δ⁹(11) when R₁₁ is a hydrogen atom, (b) 9β,11β-epoxide whenR₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁ is a single bond,and (c) a ketone when R₁₁ is an oxygen atom and . . . between C₁₁ andR₁₁ is a double bond; R₁₆ is a hydrogen atom or methyl group; Z isselected from the group consisting of a TMS, THP, methoxymethyl,t-butyldimethyl silyl and EEE group; . . . is a single or double bond; ˜indicates that the attached atom or group can be in either the α or βconfiguration; and M is a lithium, sodium, potassium, magnesium orcalcium atom.
 4. A steroid selected from the group consisting of anenimide of the formula ##STR59## and its C₃ protected forms ##STR60## oran Δ²⁰ -enamide of the formula ##STR61## and its C₃ protected forms##STR62## where R₆ is a hydrogen or fluorine atom or methyl group;R₉ isnothing, a hydrogen, fluorine or oxygen atom, which makes the C-ring(a)Δ⁹(11) when R₉ is nothing and (b) 9β-,11β-epoxide when R₉ is an oxygenatom; R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring(a) Δ⁹(11) when R₁₁ is a hydrogenatom, (b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . betweenC₁₁ and R₁₁ is a single bond, and (c) a ketone when R₁₁ is an oxygenatom and . . . . between C₁₁ and R₁₁ is a double bond; R₁₆ is a hydrogenatom or methyl group; R₂₀ is --OC--R₂₀ ' or --R₂₀ "; R₂₀ ' is alkyl of 1thru 5 carbon atoms, phenyl, phenyl substituted 0 thru 2 chlorine atoms,methyl or nitro groups; R₂₀ " is --Si(CH₃)₃ or Si(CH₃)₂ C(CH₃)₃ ; Xrefers to a hydrogen atom or nothing; Z is selected from the groupconsisting of a TMS, THP, methoxymethyl, t-butyldimethyl silyl and EEEgroup; . . . is a single or double bond; ˜ indicates that the attachedatom or group can be in either the α or β configuration; R₃ is alkyl of1 thru 5 carbon atoms with the proviso that for the ketal (Ab) and theenamine (Ac), the R₃ groups can be connected and when connected may beconnected by an oxygen or nitrogen atom; M is a lithium, sodium,potassium, magnesium or calcium atom; and W is a TMS, THP, or ethoxyethyl group.
 5. An enimide according to claim 4 where Z is selected fromthe group consisting of EEE, THP, TMS, and MEM.
 6. An enimide accordingto claim 4 where R₂₀ is selected from the group consisting of acetyl,propionyl, benzoyl, formyl, trichloroacetyl, and trifluoroacetyl.
 7. Aprocess for the preparation of a C₃ protected enimide of the formula##STR63## which comprises (1) contacting a C₃ protected17-protected-17β-cyano-17α-hydroxy steroid of the formula ##STR64## witha methylating agent and (2) contacting the reaction mixture of step (1)with an acylating or silating agent whereR₆ is a hydrogen or fluorineatom, methyl or methylene group; R₉ is nothing, a hydrogen, fluorine oroxygen atom, which makes the C-ring(a) Δ⁹(11) when R₉ is nothing and (b)9β,11β-epoxide when R₉ is an oxygen atom; R₁₁ is a hydrogen or oxygenatom, two hydrogen atoms, or α- or β-hydroxyl group which makes theC-ring(a) Δ⁹(11) when R₁₁ is a hydrogen atom, (b) 9β,11β-epoxide whenR₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁ is a single bond,and (c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ andR₁₁ is a double bond; R₁₆ is a hydrogen atom or methyl group; R₂₀ is--OC--R₂₀ ' or --R₂₀ "; R₂₀ ' is alkyl of 1 thru 5 carbon atoms, phenyl,phenyl substituted 0 thru 2 chlorine atoms, methyl or nitro groups; R₂₀" is --Si(CH₃)₃ or Si(CH₃)₂ C(CH₃)₃ ; Z is selected from the groupconsisting of a TMS, THP, methoxymethyl, t-butyldimethyl silyl and EEEgroup; . . . is a single or double bond; ˜ indicates that the attachedatom or group can be in either the α or β configuration; R₃ is alkyl of1 thru 5 carbon atoms with the proviso that for the ketal (Ab) and theenamine (Ac), the R₃ groups can be connected and when connected may beconnected by an oxygen or nitrogen atom; M is a lithium, sodium,potassium, magnesium or calcium atom; and W is a TMS, THP, or ethoxyethyl group.
 8. A process according to claim 7 where the methylatingagent is selected from the group consisting of methyl lithium, methylmagnesium bromide, methyl magnesium chloride and methyl magnesiumiodide.
 9. A process according to claim 7 where the acylating orsilating agent is selected from the group consisting of (R₂₀)₂ O, R₂₀ J,or R₂₀ "J and J is a chlorine, bromine or iodine atom.
 10. A processaccording to claim 9 where the acylating agent is acetic anhydride oracetyl chloride.
 11. A process for the preparation of a C₃ protected Δ²⁰-enamide acylate of the formula ##STR65## which comprises contacting asteroid selected from the group consisting of a C₃ protected enimide ofthe formula ##STR66## of a C₃ protected Δ²⁰ -enamide of the formula##STR67## with a carboxylic acid of the formula R₁₇ COOH and ananhydride of the formula (R₁₇ CO)₂₀ whereR₆ is a hydrogen or fluorineatom, methyl or methylene group; R₉ is nothing, a hydrogen, fluorine oroxygen atom, which makes the C-ring(a) Δ⁹(11) when R₉ is nothing and (b)9β,11β-epoxide when R₉ is an oxygen atom; R₁₁ is a hydrogen or oxygenatom, two hydrogen atoms, or α- or β-hydroxyl group which makes theC-ring(a) Δ⁹(11) when R₁₁ is a hydrogen atom, (b) 9β,11β-epoxide whenR₁₁ is an oxygen atom and . . . . between C₁₁ and R₁₁ is a single bond,and (c) a ketone when R₁₁ is an oxygen atom and . . . . between C₁₁ andR₁₁ is a double bond; R₁₆ is a hydrogen atom or methyl group; R₁₇ is ahydrogen atom alkyl of 1 thru 5 carbon atoms, phenyl substituted withzero thru 2 chlorine atoms, trichloromethyl or trifluoromethyl groups;R₂₀ is --OC--R₂₀ ' or --R₂₀ "; R₂₀ ' is alkyl of 1 thru 5 carbon atoms,phenyl, phenyl substituted 0 thru 2 chlorine atoms, methyl or nitrogroups; R₂₀ " is --Si(CH₃)₃ or Si(CH₃)₂ C(CH₃)₃ ; Z is selected from thegroup consisting of a TMS, THP, methoxymethyl, t-butyldimethyl silyl andEEE group; . . . is a single or double bond; ˜ indicates that theattached atom or group can be in either the α or β configuration; R₃ isalkyl of 1 thru 5 carbon atoms with the proviso that for the ketal (Ab)and the enamine (Ac), the R₃ groups can be connected and when connectedmay be connected by an oxygen or nitrogen atom; M is a lithium, sodium,potassium, magnesium or calcium atom; and W is a TMS, THP, or ethoxyethyl group.
 12. A process according to claim 11 where R₁₇ is methyl,ethyl or phenyl.
 13. A process for the preparation of a C₃ protected Δ²⁰-enamide of the formula ##STR68## which comprises contacting a C₃-protected enimide of the formula ##STR69## with an acid or base whereR₆ is a hydrogen or fluorine atom, methyl or methylene group;R₉ isnothing, a hydrogen, fluorine or oxygen atom, which makes the C-ring(a)Δ⁹(11) when R₉ is nothing and (b) 9β,11β-epoxide when R₉ is an oxygenatom; R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group which makes the C-ring(a) Δ⁹(11) when R₁₁ is a hydrogenatom, (b) 9β,11β-epoxide when R₁₁ is an oxygen atom and . . . . betweenC₁₁ and R₁₁ is a single bond, and (c) a ketone when R₁₁ is an oxygenatom and . . . . between C₁₁ and R₁₁ is a double bond; R₁₆ is a hydrogenatom or methyl group; R₂₀ is --OC--R₂₀ ' or --R₂₀ "; R₂₀ ' is alkyl of 1thru 5 carbon atoms, phenyl, phenyl substituted 0 thru 2 chlorine atoms,methyl or nitro groups; R₂₀ " is --Si(CH₃)₃ or Si(CH₃)₂ C(CH₃)₃ ; Z isselected from the group consisting of a TMS, THP, methoxymethyl,t-butyldimethyl silyl and EEE group; . . . is a single or double bond; ˜indicates that the attached atom or group can be in either the α or βconfiguration; R₃ is alkyl of 1 thru 5 carbon atoms with the provisothat for the ketal (Ab) and the enamine (Ac), the R₃ groups can beconnected and when connected may be connected by an oxygen or nitrogenatom; M is a lithium, sodium, potassium, magnesium or calcium atom; andW is a TMS, THP, or ethoxy ethyl group.
 14. A process according to claim13 where the acid is a Lewis acid or carboxylic acid.
 15. A processaccording to claim 14 where the acid is selected from the groupconsisting of acetic, propionic, benzoic or citric acid.
 16. A processaccording to claim 13 where the base is selected from the groupconsisting of DBU, DBN, amidine bases of the formula ##STR70## andguanidine bases of the formula ##STR71## where R_(a) is alkyl of 1 thru7 carbon atoms, cycloalkyl of 5 thru 7 carbon atoms, phenyl substitutedwith 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂ where with the amine theR₁₀₅ 's can be the same or different and can be combined to form acyclic secondary amine selected from the group consisting of piperidine,pyrrolidine and morpholine;R_(g) is R_(a), a hydrogen atom or phenyl;R₁₀₁ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbonatoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂where with the amine the R₁₀₅ 's can be the same or different and can becombined to form a cyclic secondary amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine; R₁₀₂ is alkyl of 1thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbon atoms, phenylsubstituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂ where with theamine the R₁₀₅ 's can be the same or different and can be combined toform a cyclic secondary amine selected from the group consisting ofpiperidine, pyrrolidine and morpholine; R₁₀₃ is alkyl of 1 thru 7 carbonatoms, cycloalkyl of 5 thru 7 carbon atoms, phenyl substituted with 1thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂ where with the amine the R₁₀₅ 'scan be the same or different and can be combined to form a cyclicsecondary amine selected from the group consisting of piperidine,pyrrolidine and morpholine; R₁₀₄ is alkyl of 1 thru 7 carbon atoms,cycloalkyl of 5 thru 7 carbon atoms, phenyl substituted with 1 thru 3--R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂ where with the amine the R₁₀₅ 's can bethe same or different and can be combined to form a cyclic secondaryamine selected from the group consisting of piperidine, pyrrolidine andmorpholine; R₁₀₆ is alkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru7 carbon atoms, phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or--N(R₁₀₅)₂ where with the amine the R₁₀₅ 's can be the same or differentand can be combined to form a secondary amine selected from the groupconsisting of piperidine, pyrrolidine or morpholine with the provisothat R₁₀₆ and R₁₀₇ combined cannot have more than 14 carbon atoms; R₁₀₆and R₁₀₇ can be combined to form a secondary cyclic amine selected fromthe group consisting of piperidine, pyrrolidine and morpholine; R₁₀₇ isalkyl of 1 thru 7 carbon atoms, cycloalkyl of 5 thru 7 carbon atoms,phenyl substituted with 1 thru 3 --R₁₀₀, --OR₁₀₅ or --N(R₁₀₅)₂ wherewith the amine the R₁₀₅ 's can be the same or different and can becombined to form a secondary amine selected from the group consisting ofpiperidine, pyrrolidine or morpholine with the proviso that R₁₀₆ andR₁₀₇ combined cannot have more than 14 carbon atoms; R₁₀₆ and R₁₀₇ canbe combined to form a secondary cyclic amine selected from the groupconsisting of piperidine, pyrrolidine and morpholine.
 17. A17β-cyano-17α-hydroxy steroid according to claim 1 which is selectedfrom the group consisting of17β-cyano-11β,17α-dihydroxyandrosta-1,4-dien-3-one and17β-cyano-11β,17α-dihydroxy-6α-methylandrosta-1,4-dien-3-one.
 18. Anenimide according to claim 4 which is selected from the group consistingof a 17α-(α-ethoxyethyl)-ether-20-acetylaminopregn-5-en-3-ethylidineketal, and17α-(α-ethoxyethyl)-ether-20-trifluoroacetylaminopregn-5-ene-3-ethylidineketal.